Search

Manganese is embryotoxic and fetotoxic in mammals. The aim of this study was to determine whether the day of exposure would modify the developmental toxicity of manganese (II). Pregnant Swiss mice were given single sc doses of 50 mg manganese chloride tetrahydrate/kg on day 9, 10, 11 or 12 of gestation. No maternal deaths, abortions or early deliveries were observed. Dams were killed on gestational day 18 and the uterine contents examined. Embryotoxicity, evidenced by significant increases in number of late resorptions and in percentage of postimplantation loss, was especially relevant in groups dosed on gestational days 9 or 10. Fetotoxicity (reduced fetal body weight and increased incidence of skeletal defects) was also especially remarkable from doses on days 9 or 10 of gestation. However, no teratogenic effects were noted in any group. Although mouse conceptus are adversely affected by sc exposure to manganese on any of the gestational days 9-12, days 9 and 10 of gestation are the most sensitive for manganese-induced embryo/fetal toxicity in mice.

Cyclohexanediaminetetraacetic acid (CDTA), an effective antagonist for the treatment of zinc, lead, and manganese poisoning was evaluated for maternal and developmental toxicity in pregnant Swiss mice. CDTA was given intraperitoneally on gestation days 6-15 at doses of 0, 270, 540, and 1080 mg/kg/day. On gestational day 18, the fetuses were examined for external, visceral, and skeletal malformations and variations. Treatment with CDTA at 1080 mg/kg/day resulted in a high level of maternal deaths, as well as less severe clinical signs (significant reduction in weight gain and food consumption). Increased resorptions, fetal deaths, and decreased number of live fetuses per litter were observed at 1080 mg/kg/day. Mean fetal body weights were also significantly decreased in this group. At 1080 mg/kg/day, CDTA caused external malformations, while the development of skeletal tissues was less affected. The no observable adverse effect level (NOAEL) for maternal and developmental toxicity of CDTA in mice was 540 mg/kg/day. Analyses of maternal and fetal tissues revealed only slight effects of CDTA on concentrations of calcium, magnesium, zinc, copper and iron. According to these results, the alterations in mineral metabolism should not be the major reason for CDTA-induced developmental toxicity.

The influence of lactate on the potential developmental toxicity of high doses of aluminum (57.5 mg/kg/day) was evaluated. Three groups of pregnant Swiss mice were given by gavage daily doses of Al(OH)3 (166 mg/kg), aluminum lactate (627 mg/kg), or Al(OH)3 (166 mg/kg) concurrent with lactic acid (570 mg/kg) on gestational days 6-15. An additional group of pregnant mice received lactic acid (570 mg/kg) during the same period. Cesarean sections were performed on gestation day 18, and live fetuses were sexed, weighed and examined for morphological defects. Maternal toxicity was observed in the groups treated with aluminum lactate, and Al(OH)3 concurrent with lactic acid. The reproductive data did not show embryotoxic effects in any group, whereas fetal body weight was significantly reduced in the aluminum lactate group. In this group, morphological changes included cleft palate and an increased incidence of parietals with delayed ossification. Although not statistically significant, the incidence of skeletal variations was also increased in the group given Al(OH)3 concurrent with lactic acid. Taken together the present data, as well as the results of previous studies strongly suggest that the consumption of high doses of aluminum-containing compounds should be avoided during pregnancy.

Diethylenetriaminepentaacetic acid (DTPA), ethylenglycolbis-(beta-amino-ethylether)-N,N-tetraacetic acid (EGTA), tartaric acid, KRYPTOFIX 222, and KRYPTOFIX 5 were evaluated for their efficacy in mobilization of strontium from the body of mice which had received 20 sc injections of strontium nitrate (95 mg/kg/injection) for 4 w. Twenty-four hours after the last strontium injection, ip administration of 1 of the various chelators or 0.9% saline was initiated and continued daily for 5 d. Mice were housed in metabolic cages, and urine and feces were collected daily for 5 d. After this period, the animals were killed and tissues removed. Tartaric acid, KRYPTOFIX 222, and KRYPTOFIX 5 had no effect on urinary or fecal strontium elimination, whereas DTPA and EGTA significantly decreased the fecal strontium excretion. The concentration of strontium in bone was only lowered in tartaric-treated mice. This study indicates the use of the above chelators is not an effective treatment to enhance the removal of strontium following repeated parenteral strontium administration.

The effects of repeated ip administration of diethylenetriamine-pentaacetic acid (DTPA), ethylenglycol-bis-(-amino-ethlylether)-N,N'-tetraacetic acid (EGTA), Kryptofix 222, tartaric acid, and Kryptofix 5 on strontium (Sr) excretion and Sr levels in selected mouse tissues were investigated following semichronic strontium nitrate ingestion (284 mg/kg/day) for four weeks. Chelating agents were injected daily for five days at 1/4 of their respective LD50 in two equally divided doses. Only Kryptofix 5 significantly increased the amount of Sr excreted into urine, whereas none of the chelators enhanced the fecal Sr elimination. A significant decrease in the concentration of Sr in bone, the primary tissue of Sr deposition, was observed after treatment with EGTA. Under these experimental conditions, none of the chelators tested was able to remove significant amounts of Sr following Sr ingestion for four weeks.

Effects of ip treatment with diethylenetriaminepentaacetic acid (DTPA), and cyclohexanediaminetetraacetic acid (CDTA) on the zinc (Zn) excretion and Zn levels in selected mouse organs and tissues were assessed after mice were offered deionized water containing zinc acetate dihydrate (108 mg/kg/day) as the sole drinking fluid for 4 weeks. Following this period, the Zn-containing water was replaced by tap water and therapy with DTPA or CDTA was initiated. The animals received 6 injections of chelators or 0.9% saline (control group) on alternate days for 2 weeks of treatment. The dose of chelating agents was approximately equal to 1/4 of their respective ip LD50 values. Mice were housed in metabolic cages, and urine and feces were collected 24 hr after the first, fourth and sixth administration of the chelators. Six animals in each group were sacrificed at the same days. Although feces was the predominant route of elimination for Zn, only DTPA significantly increased the fecal excretion of Zn after the first administration of chelator. Treatment with DTPA or CDTA resulted in a significant decrease in the concentration of Zn in brain, spleen, and heart after the first injection. DTPA was consistently the most effective in increasing the urinary and fecal excretion of Zn and reducing the concentration of the metal found in various tissues. CDTA would be considered as a possible alternative.

The effect of increasing the time interval between acute zinc exposure and chelation therapy was studied in male Swiss mice. Cyclohexanediaminetetraacetic acid (CDTA), and diethylenetriaminepentaacetic acid (DTPA) were administered ip at 0, 0.25, 0.5, 2, 12, or 24 hr after ip administration of 0.40 mmol/kg of zinc acetate dihydrate. Chelating agents were given at doses equal to 1/3 of their respective LD50 values. Effectiveness of chelation therapy was determined by measuring the ability of the chelators to increase the elimination of zinc and decrease the concentration of the metal in various tissues. Treatment with DTPA or CDTA increased significantly the urinary and fecal excretion of zinc when the chelators were administered at various times following zinc exposure. The greatest antidotal efficacy of the chelating agents was observed at 0.50 hr after zinc injection. Nevertheless, the effectiveness of DTPA and CDTA was decreasing when the chelators were administered later. DTPA was more effective than CDTA in the prevention of acute zinc intoxication. CDTA would be considered as a possible alternative.